Genetic mouse models based on genetic susceptibility are still in their infancy. We continue to study the roles of susceptibility genes in cognitive processing, neuronal function, and signal transduction in the brain during development. Examining candidate risk genes interactions with environmental factors, will most likely give better understanding of the molecular mechanisms of the pathophysiology of schizophrenia, reveal the molecular basis of normal cognitive function and human brain development, and guide us to novel antipsychotic therapies. [unreadable] [unreadable] In our evaluation of COMT, our group examined enzyme activity and protein expression in prefrontal cortex (PFC) in 6 age groups of normal controls from neonates to the aged. We found a significant increase in COMT enzyme activity from neonate to adulthood and this is paralleled by increases in protein expression. Additionally, COMT protein expression is related to the val158met genotype. These increases may reflect changes in the PFC dopamine system and stresses the increasing importance of COMT for PFC dopamine regulation during maturation. The increasing body of evidence which shows the COMT val/met polymorphism impact on PF cognition, raises the possibility of a novel pharmacological approach for the treatment of PF lobe executive dysfunction. Efforts to enhance prefrontal-related cognition using catecholamine stimulant drugs, has been unsatisfactory. In another study, a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT genotype was performed. Our group measured COMT enzyme activity in peripheral blood and found significant drug effects on measures of executive function and verbal episodic memory and a significant drug effect by genotype interaction, such that COMT val/val improved, whereas met/met worsened on the drug, Tolcapone. Functional magnetic resonance imaging (fMRI) revealed a significant tolcapone-induced improvement in the efficiency of information processing in PFC during a working memory test. This study demonstrates enhancement of PF cortical function in normal human subjects with a non-stimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of dopamine signaling in the PFC.[unreadable] [unreadable] Human studies have primarily focused on the COMT val/met functional mutation. COMT-val leads to higher COMT protein levels and enzymatic activity compared with COMT-met. In general, genetic variations in human COMT have been associated with physiological functions and behavioral phenotypes related to PFC and hippocampal information processing, including cognition, anxiety, obsessive compulsive disorder and pain sensitivity. However doubts about clinical impact still exists, because of the complexity of human COMT polymorphism and clinical variability. This year, we generated a transgenic mice overexpressing human COMT-val (Val-tg) and compared them with mice without a functional COMT and normal mice which contain COMT-leu. Increased COMT activity in Val-tg mice resulted in impairment in attentional set shifting abilities, and working and recognition memory. There was no change in acquisition or reversal learning. COMT Val-tg mice also showed recognition memory deficits. However, acute treatment with amphetamine, which increases dopamine levels, restored recognition memory performance in COMT Val-tg mice but worsened performance control. Despite the COMT genotype effects on working memory processes, COMT Val-tg mice showed normal performance in tasks involving a regularly repeated sequence of events rather than trial-specific experience. These results highlight the COMT gene as a critical factor in the regulation of executive memory processes. With regards to environmental stressors, COMT null mice ( -/-) were the best performers under low stress conditions, whereas COMT heterozygous mice (+/-) performed best under challenging conditions. It appears that mild uncontrolled stress impairs PFC working memory functions in human and animals. The heterozygous advantage may be additional evidence of the relationship between cortical dopamine levels and cognition. These genetically altered mice showed dramatic effects of COMT on emotional and autonomic arousal. We have demonstrated that increased COMT activity is a risk factor for cortically dependent cognitive dysfunctions but a protective factor when under stress, whereas COMT reduction enhances working memory processes but results in exaggerated stress reactions. The COMT transgenic and knock-out mice show notable aspects of human behaviors associated with COMT mutations and establish biologic validity of these associations. Our COMT mouse model establishes that a common genetic factor can be involved in diverse clinical disorders characterized by abnormal cognitive processing and reaction to stress which represents a promising new animal model for testing cognitive and stress related therapies. Finally, these results demonstrate an intriguing functional trade-off between genetic variation that concurrently results in more efficient cognitive behaviors and less adaptive affective behaviors.[unreadable] [unreadable] Another gene, neuregulin (NRG1) is essential for the development and function of multiple organ systems and its dysregulation has been linked to diseases such as cancer and schizophrenia. Many human genes are known to produce more than one protein isoform through the use of alternative molecular events that determine the efficient and accurate initiation of gene transcription. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizophrenia-related genetic variants. This study isolated and characterized full-length NRG1 type IV DNAs from the adult and fetal human brain and identified novel splice variants of NRG1. NRG1 type IV and a putative type IV protein isoform were found to be brain-specific and abundantly expressed in the fetal brain. In addition, 2 novel type IV variants were identified. Our data suggest that type IV is a unique brain-specific NRG1 that is differentially expressed, processed during early development, and is translated while its expression is regulated by a mutation in a regulatory element associated with risk for schizophrenia.